In the US, Lunesta (eszopiclone systemic) is a member of the drug class miscellaneous anxiolytics, sedatives and hypnotics and is used to treat Insomnia.
US matches:
Eszopiclone is reported as an ingredient of Lunesta in the following countries:
International Drug Name Search
Parkisan may be available in the countries listed below.
Trihexyphenidyl hydrochloride (a derivative of Trihexyphenidyl) is reported as an ingredient of Parkisan in the following countries:
International Drug Name Search
Generic Name: desipramine (des IP ra meen)
Brand Names: Norpramin
Desipramine is a tricyclic antidepressant. Desipramine affects chemicals in the brain that may become unbalanced.
Desipramine is used to treat symptoms of depression.
Desipramine may also be used for other purposes not listed in this medication guide.
You may have thoughts about suicide when you first start taking an antidepressant, especially if you are younger than 24 years old. Your doctor will need to check you at regular visits for at least the first 12 weeks of treatment.
Treatments for depression are getting better everyday and there are things you can start doing right away.
If you have any of these other conditions, you may need a dose adjustment or special tests to safely take desipramine:
heart disease, or a history of heart attack, stroke, or seizures;
a family history of sudden death related to a heart rhythm disorder;
bipolar disorder (manic-depression);
schizophrenia or other mental illness;
liver disease;
overactive thyroid;
diabetes (desipramine may raise or lower blood sugar);
glaucoma; or
problems with urination.
You may have thoughts about suicide when you first start taking an antidepressant, especially if you are younger than 24 years old. Tell your doctor if you have worsening symptoms of depression or suicidal thoughts during the first several weeks of treatment, or whenever your dose is changed.
Your family or other caregivers should also be alert to changes in your mood or symptoms. Your doctor will need to check you at regular visits for at least the first 12 weeks of treatment.
Older adults may be more likely to have side effects from this medication.
Take this medication exactly as it was prescribed for you. Do not take the medication in larger amounts, or take it for longer than recommended by your doctor. Your doctor may occasionally change your dose to make sure you get the best results from this medication. Follow the directions on your prescription label.
If you need to have any type of surgery, tell the surgeon ahead of time that you are taking desipramine. You may need to stop using the medicine for a short time.
Take the missed dose as soon as you remember. If it is almost time for your next dose, skip the missed dose and take the medicine at the next regularly scheduled time. Do not take extra medicine to make up the missed dose.
Grapefruit and grapefruit juice may interact with desipramine. Discuss the use of grapefruit products with your doctor before increasing or decreasing the amount of grapefruit products in your diet.
Call your doctor at once if you have any new or worsening symptoms such as: mood or behavior changes, anxiety, panic attacks, trouble sleeping, or if you feel impulsive, irritable, agitated, hostile, aggressive, restless, hyperactive (mentally or physically), more depressed, or have thoughts about suicide or hurting yourself.
fast, pounding, or uneven heart rate;
seizure (convulsions);
chest pain or heavy feeling, pain spreading to the arm or shoulder, nausea, general ill feeling;
sudden numbness or weakness, especially on one side of the body;
sudden headache, problems with vision, speech, or balance;
easy bruising or bleeding, unusual weakness;
tremors, restless muscle movements in your eyes, tongue, jaw, or neck;
very stiff (rigid) muscles, high fever, sweating, confusion, tremors, feeling like you might pass out;
urinating less than usual or not at all;
extreme thirst with headache, nausea, vomiting, and weakness;
skin rash, severe tingling or numbness, pain and muscle weakness; or
nausea, stomach pain, low fever, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes).
Less serious side effects may include:
vomiting, constipation;
dry mouth, unpleasant taste;
weakness, lack of coordination;
feeling anxious, restless, dizzy, or drowsy;
sleep problems (insomnia), nightmares;
blurred vision, trouble concentrating, headache, ringing in your ears;
breast swelling (in men or women); or
decreased sex drive, impotence, or difficulty having an orgasm.
This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
Before taking desipramine, tell your doctor if you have used an "SSRI" antidepressant in the past 5 weeks, such as citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac, Sarafem), fluvoxamine (Luvox), paroxetine (Paxil), or sertraline (Zoloft).
Tell your doctor about all other medicines you use, especially:
cimetidine (Tagamet); or
heart rhythm medications such as flecainide (Tambocor), propafenone (Rhythmol), or quinidine (Cardioquin, Quinidex, Quinaglute).
This list is not complete and there are many other medicines that can interact with desipramine. Tell your doctor about all the prescription and over-the-counter medications you use. This includes vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start using a new medication without telling your doctor. Keep a list with you of all the medicines you use and show this list to any doctor or other healthcare provider who treats you.
See also: Norpramin side effects (in more detail)
Generic Name: valproic acid (Oral route)
val-PROE-ik AS-id
Hepatic failure resulting in fatalities has occurred in patients receiving valproic acid and its derivatives. Children under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity. Patients should be monitored closely and liver function tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first six months. Life-threatening pancreatitis has been reported in both children and adults receiving valproate. If pancreatitis is diagnosed, valproate should ordinarily be discontinued. Valproate can produce teratogenic effects such as neural tube defects (eg, spina bifida). Accordingly, the use of valproate products in women of childbearing potential requires that the benefits of its use be weighed against the risk of injury to the fetus .
Hepatotoxicity (some cases fatal), usually occurring during the first 6 months of treatment, has been reported in patients receiving valproic acid and its derivatives. Children under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity. Monitor patients closely, and perform liver function tests prior to therapy and at frequent intervals thereafter. Valproate can produce teratogenic effects such as neural tube defects (eg, spina bifida). Accordingly, the use of divalproex sodium in women of childbearing potential requires that the benefits of its use be weighed against the risk of injury to the fetus. Life-threatening pancreatitis has been reported in both children and adults receiving valproate. If pancreatitis is diagnosed, valproate should ordinarily be discontinued .
In the U.S.
In Canada
Available Dosage Forms:
Therapeutic Class: Antimanic
Pharmacologic Class: Histone Deacetylase Inhibitor
Chemical Class: Valproic Acid (class)
Valproic acid is used alone or together with other medicines to control certain types of seizures (convulsions) in the treatment of epilepsy. This medicine is an anticonvulsant that works in the brain tissue to stop seizures.
Valproic acid is also used to treat the manic phase of bipolar disorder (manic-depressive illness), and helps prevent migraine headaches.
This medicine is available only with your doctor's prescription.
In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:
Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.
Appropriate studies performed to date have not demonstrated pediatric-specific problems that would limit the usefulness of valproic acid in children. However, safety and efficacy have not been established in children with epilepsy below 10 years of age; and in children with migraine below 12 years of age. Because of valproic acid's toxicity, use in children below 2 years of age requires extreme caution.
Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of valproic acid in the elderly. However, elderly patients are more likely to have unwanted effects (e.g., tremors or unusual drowsiness), which may require an adjustment in the dose for patients receiving valproic acid.
| Pregnancy Category | Explanation | |
|---|---|---|
| All Trimesters | D | Studies in pregnant women have demonstrated a risk to the fetus. However, the benefits of therapy in a life threatening situation or a serious disease, may outweigh the potential risk. |
There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.
Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.
Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.
Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.
Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.
The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:
This section provides information on the proper use of a number of products that contain valproic acid. It may not be specific to Stavzor. Please read with care.
Take this medicine exactly as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered.
This medicine comes with a medication guide and patient information insert. Read and follow the instructions in the insert carefully. Ask your doctor if you have any questions.
Swallow the delayed-release capsules and oral capsules whole with a full glass of water. Do not split, crush, or chew it. You may take this medicine with food.
The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.
The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.
If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.
Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.
Keep out of the reach of children.
Do not keep outdated medicine or medicine no longer needed.
Ask your healthcare professional how you should dispose of any medicine you do not use.
It is very important that your doctor check your progress closely while you are using this medicine to see if it is working properly and to allow for a change in the dose. Blood tests may be needed to check for any unwanted effects.
Using this medicine while you are pregnant (especially during first trimester) can harm your unborn baby. Use an effective form of birth control to keep from getting pregnant. If you think you have become pregnant while using the medicine, tell your doctor right away.
It is very important to take folic acid before getting pregnant and during early pregnancy to lower chances of harmful side effects to your unborn baby. Ask your doctor or pharmacist for help if you are not sure how to choose a folic acid product.
Liver problems may occur while you are using this medicine. Stop using this medicine and check with your doctor right away if you are having more than one of these symptoms: abdominal pain or tenderness; clay-colored stools; dark urine; decreased appetite; fever; headache; itching; loss of appetite; nausea and vomiting; skin rash; swelling of the feet or lower legs; unusual tiredness or weakness; or yellow eyes or skin.
Pancreatitis may occur while you are using this medicine. Tell your doctor right away if you have sudden and severe stomach pain, chills, constipation, nausea, vomiting, fever, or lightheadedness.
Check with your doctor right away if you are having unusual drowsiness, dullness, tiredness, weakness or feelings of sluggishness, changes in mental status, or vomiting. These may be symptoms of a serious condition called hyperammonemic encephalopathy.
Valproic acid may cause some people to become dizzy, lightheaded, drowsy, or less alert than they are normally. Make sure you know how you react to this medicine before you drive, use machines, or do anything else that could be dangerous if you are dizzy or not alert.
Do not stop taking this medicine without first checking with your doctor. Your doctor may want you to gradually reduce the amount you are using before stopping completely.
Before you have any medical tests, tell the medical doctor in charge that you are taking this medicine. The results of some tests may be affected by this medicine.
Valproic acid may cause serious allergic reactions that affect several parts of the body (e.g., liver or kidney). Check with your doctor right away if you have more than one of the following symptoms: fever; dark urine; headache; rash; stomach pain; swollen lymph glands in the neck, armpit, or groin; unusual tiredness; or yellow eyes or skin.
This medicine will add to the effects of alcohol and other CNS depressants (medicines that make you drowsy or less alert). Some examples of CNS depressants are antihistamines or medicine for hay fever or colds; sedatives, tranquilizers, or sleeping medicine; prescription pain medicine or narcotics; barbiturates or medicine for seizures; muscle relaxants; or anesthetics, including some dental anesthetics. Check with your doctor before taking any of the above while you are taking this medicine.
Check with your doctor if you have unusual drowsiness, dullness, tiredness, weakness; or feeling of sluggishness; confusion; low body temperature; or loss of consciousness while taking this medicine.
Valproic acid may cause some people to be agitated, irritable, or display other abnormal behaviors. It may also cause some people to have suicidal thoughts and tendencies or to become more depressed. If you notice any of these adverse effects, tell your doctor right away.
Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.
Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.
Check with your doctor immediately if any of the following side effects occur:
Get emergency help immediately if any of the following symptoms of overdose occur:
Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:
Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.
Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.
See also: Stavzor side effects (in more detail)
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PREDFOAM
Prednisolone
as Prednisolone Metasulphobenzoate Sodium
1. What Predfoam is and what it is used for
2. Before you use Predfoam
3. How to use Predfoam
4. Possible side effects
5. How to store Predfoam
6. Further information
Predfoam is a foam enema which is inserted into the rectum. Predfoam belongs to a group of medicines called corticosteroids which are used to reduce inflammation.
Predfoam is used to treat ulcerative colitis (inflammation of the bowels) and may be used to treat proctitis (inflammation of the rectum).
If you think this may apply to you speak to your doctor.
Predfoam is for application in the rectum only.
It is not advisable to use Predfoam for a long period of time, but your doctor will be aware of this.
You can use Predfoam whilst taking other medicines.
Ask your doctor for advice before using Predfoam if you are pregnant or breast-feeding.
Always use Predfoam exactly as your doctor has told you. You should check with your doctor if you are not sure.
Predfoam is not recommended for use in children (i.e. those under 18 years old).
One metered-dose of Predfoam should be inserted rectally, using one of the applicator nozzles provided, once or twice daily for 2 weeks. Your doctor may decide to extend the treatment for a further 2 weeks.
Predfoam has been designed for your maximum comfort and ease of use. Read these instructions carefully before using Predfoam for the first time.
If you find it difficult to use Predfoam in a standing position an alternative is to administer while lying on your side with both legs bent up.
1. Shake before use.
2. When using for the first time remove and discard the small plastic safety tag from under the button.
3. Carefully push an applicator nozzle onto the side arm of the canister. Line-up semi-circular cut-out on cap with nozzle.
4. The easiest way to use Predfoam is to stand with one foot raised on a chair and gently insert the nozzle tip into your rectum. It may help if you smear the nozzle with lubricating jelly before insertion.
5. Important: Holding the canister with the dose button pointing down, press the button on the canister firmly and release. Only press the button once otherwise you will exceed the recommended dose.
Note: the canister will only work when held with the dose button pointing down.
Foam is expelled when the button is released.
Dispose of the used nozzle in the plastic bag provided – the nozzles will not flush down toilets.
The used nozzles should be disposed of in the plastic bag provided.
Do not worry if you miss a dose of Predfoam. Administer Predfoam as soon as you remember and then use your next dose at the usual time. Do not use more than 2 doses in one day.
Overdosage by this route is unlikely, but if someone else takes your medicine or it is used incorrectly take the canister to your doctor and ask for advice.
If you have any further questions on the use of this product, ask your doctor.
Normally, there are no side effects associated with the use of Predfoam. However, if you think that Predfoam is causing you any unusual discomfort or problems, please contact your doctor or pharmacist.
Keep out of the reach and sight of children.
Do not use Predfoam after the expiry date stated on the carton and canister after ‘Use By End’. The expiry date refers to the last day of that month.
Predfoam is supplied in a pressurised container containing a flammable propellant. Do not store above 25˚C. Protect from sunlight and do not expose to temperatures above 50˚C. Do not pierce or burn even after use. Do not spray on naked flame or any incandescent material. Do not store in a refrigerator.
Discard after 14 doses have been used.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.
The active substance is prednisolone metasulphobenzoate sodium. Each metered dose contains 31.4mg of the active ingredient (equivalent to 20.0mg of prednisolone).
The other ingredients are non-ionic emulsifying wax, cetostearyl alcohol, oleyl alcohol, technical white oil, phenoxyethanol, sorbic acid, polysorbate 20, disodium edetate, sodium hydroxide and purified water. The propellant in Predfoam is Butane 48.
Predfoam is supplied in a canister. Each canister contains enough product for 14 doses and comes supplied with disposable applicators and disposal bags.
This leaflet was approved in:
May 2009
Other formats:
To listen to or to request a copy of this leaflet in Braille, large print or audio please call, free of charge:
0800 198 5000 (UK only)
Please be ready to give the following information:
Product Name Predfoam
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This is a service provided by the Royal National Institute for Blind People.
Parkinane LP may be available in the countries listed below.
Trihexyphenidyl hydrochloride (a derivative of Trihexyphenidyl) is reported as an ingredient of Parkinane LP in the following countries:
International Drug Name Search
Viread 245 mg film-coated tablets
Each film-coated tablet contains 245 mg of tenofovir disoproxil (as fumarate), equivalent to 300 mg of tenofovir disoproxil fumarate, or 136 mg of tenofovir.
Excipient(s):
Each tablet contains 164 mg lactose monohydrate.
For a full list of excipients, see section 6.1.
Film-coated tablet.
Light blue, almond-shaped, film-coated tablets, of dimensions 16.8 mm x 10.3 mm, debossed on one side with “GILEAD” and “4331” and on the other side with “300”.
HIV-1 infection
Viread is indicated in combination with other antiretroviral medicinal products for the treatment of HIV-1 infected adults aged 18 years and over.
The demonstration of the benefit of Viread in HIV-1 infection is based on results of one study in treatment-naïve patients, including patients with a high viral load (> 100,000 copies/ml) and studies in which Viread was added to stable background therapy (mainly tritherapy) in antiretroviral pre-treated patients experiencing early virological failure (< 10,000 copies/ml, with the majority of patients having < 5,000 copies/ml).
The choice of Viread to treat antiretroviral-experienced patients with HIV-1 infection should be based on individual viral resistance testing and/or treatment history of patients.
Hepatitis B infection
Viread is indicated for the treatment of chronic hepatitis B (see section 5.1) in adults with:
• compensated liver disease, with evidence of active viral replication, persistently elevated serum alanine aminotransferase (ALT) levels and histological evidence of active inflammation and/or fibrosis
• decompensated liver disease (see sections 4.4, 4.8 and 5.1).
Therapy should be initiated by a physician experienced in the management of HIV infection and/or treatment of chronic hepatitis B.
Posology
Adults: The recommended dose of Viread for the treatment of HIV or for the treatment of chronic hepatitis B is 245 mg (one tablet) once daily taken orally with food.
Chronic hepatitis B: The optimal duration of treatment is unknown. Treatment discontinuation may be considered as follows:
- In HBeAg positive patients without cirrhosis, treatment should be administered for at least 6-12 months after HBe seroconversion (HBeAg loss and HBV DNA loss with anti-HBe detection) is confirmed or until HBs seroconversion or there is loss of efficacy (see section 4.4). Serum ALT and HBV DNA levels should be followed regularly after treatment discontinuation to detect any late virological relapse.
- In HBeAg negative patients without cirrhosis, treatment should be administered at least until HBs seroconversion or there is evidence of loss of efficacy. With prolonged treatment for more than 2 years, regular reassessment is recommended to confirm that continuing the selected therapy remains appropriate for the patient.
If a patient misses a dose of Viread, the patient should take Viread with food as soon as possible and resume their normal dosing schedule. If a patient misses a dose of Viread and it is almost time for their next dose, the patient should not take the missed dose and simply resume the usual dosing schedule.
If the patient vomits within 1 hour of taking Viread, another tablet should be taken. If the patient vomits more than 1 hour after taking Viread they do not need to take another dose.
Special populations
Elderly: No data are available on which to make a dose recommendation for patients over the age of 65 years (see section 4.4).
Renal insufficiency: Tenofovir is eliminated by renal excretion and the exposure to tenofovir increases in patients with renal dysfunction. There are limited data on the safety and efficacy of tenofovir disoproxil fumarate in patients with moderate and severe renal impairment (creatinine clearance < 50 ml/min) and long-term safety data has not been evaluated for mild renal impairment (creatinine clearance 50-80 ml/min). Therefore, in patients with renal impairment tenofovir disoproxil fumarate should only be used if the potential benefits of treatment are considered to outweigh the potential risks. Dose interval adjustments are recommended for patients with creatinine clearance < 50 ml/min.
Mild renal impairment (creatinine clearance 50-80 ml/min): Limited data from clinical studies support once daily dosing of tenofovir disoproxil fumarate in patients with mild renal impairment.
Moderate renal impairment (creatinine clearance 30-49 ml/min): Administration of 245 mg tenofovir disoproxil (as fumarate) every 48 hours is recommended based on modelling of single-dose pharmacokinetic data in non-HIV and non-HBV infected subjects with varying degrees of renal impairment, including end-stage renal disease requiring haemodialysis, but has not been confirmed in clinical studies. Therefore, clinical response to treatment and renal function should be closely monitored in these patients (see sections 4.4 and 5.2).
Severe renal impairment (creatinine clearance < 30 ml/min) and haemodialysis patients: Adequate dose adjustments cannot be applied due to lack of alternative tablet strengths, therefore use in this group of patients is not recommended. If no alternative treatment is available, prolonged dose intervals may be used as follows:
Severe renal impairment: 245 mg tenofovir disoproxil (as fumarate) may be administered every 72-96 hours (dosing twice a week).
Haemodialysis patients: 245 mg tenofovir disoproxil (as fumarate) may be administered every 7 days following completion of a haemodialysis session*.
These dose adjustments have not been confirmed in clinical studies. Simulations suggest that the prolonged dose interval is not optimal and could result in increased toxicity and possibly inadequate response. Therefore clinical response to treatment and renal function should be closely monitored (see sections 4.4 and 5.2).
* Generally, once weekly dosing assuming three haemodialysis sessions per week, each of approximately 4 hours duration or after 12 hours cumulative haemodialysis.
No dosing recommendations can be given for non-haemodialysis patients with creatinine clearance < 10 ml/min.
Hepatic impairment: No dose adjustment is required in patients with hepatic impairment (see sections 4.4 and 5.2).
If Viread is discontinued in patients with chronic hepatitis B with or without HIV co-infection, these patients should be closely monitored for evidence of exacerbation of hepatitis (see section 4.4).
Paediatric population: Viread is not recommended for use in children.
The clinical data available in HIV-1 infected adolescents are inadequate to support the use of tenofovir disoproxil fumarate in this population (see sections 4.4 and 5.1) and no data are currently available in younger children.
No data are currently available in paediatric patients infected with chronic hepatitis B.
Method of administration
Viread tablets should be taken once daily, orally with food.
In exceptional circumstances in patients having particular difficulty in swallowing, Viread can be administered following disintegration of the tablet in at least 100 ml of water, orange juice or grape juice.
Hypersensitivity to the active substance or to any of the excipients.
General: HIV antibody testing should be offered to all HBV infected patients before initiating tenofovir disoproxil fumarate therapy (see below Co-infection with HIV-1 and hepatitis B).
Patients must be advised that tenofovir disoproxil fumarate has not been proven to prevent the risk of transmission of HIV or HBV to others through sexual contact or contamination with blood. Appropriate precautions must continue to be used.
Viread contains lactose monohydrate. Consequently, patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.
Co-administration of other medicinal products:
- Viread should not be administered concomitantly with other medicinal products containing tenofovir disoproxil fumarate.
- Viread should not be administered concomitantly with adefovir dipivoxil.
- Co-administration of tenofovir disoproxil fumarate and didanosine is not recommended. Co-administration of tenofovir disoproxil fumarate and didanosine results in a 40-60% increase in systemic exposure to didanosine that may increase the risk of didanosine-related adverse reactions (see section 4.5). Rarely, pancreatitis and lactic acidosis, sometimes fatal, have been reported. Co-administration of tenofovir disoproxil fumarate and didanosine at a dose of 400 mg daily has been associated with a significant decrease in CD4 cell count, possibly due to an intracellular interaction increasing phosphorylated (i.e. active) didanosine. A decreased dosage of 250 mg didanosine co-administered with tenofovir disoproxil fumarate therapy has been associated with reports of high rates of virological failure within several tested combinations for the treatment of HIV-1 infection.
Triple therapy with nucleosides/nucleotides: There have been reports of a high rate of virological failure and of emergence of resistance at an early stage in HIV patients when tenofovir disoproxil fumarate was combined with lamivudine and abacavir as well as with lamivudine and didanosine as a once daily regimen.
Renal function: Tenofovir is principally eliminated via the kidney. Renal failure, renal impairment, elevated creatinine, hypophosphataemia and proximal tubulopathy (including Fanconi syndrome) have been reported with the use of tenofovir disoproxil fumarate in clinical practice (see section 4.8).
Renal safety with tenofovir has only been studied to a very limited degree in patients with impaired renal function (creatinine clearance < 80 ml/min).
It is recommended that creatinine clearance is calculated in all patients prior to initiating therapy with tenofovir disoproxil fumarate and renal function (creatinine clearance and serum phosphate) is also monitored every four weeks during the first year, and then every three months. In patients at risk for renal impairment, including patients who have previously experienced renal events while receiving adefovir dipivoxil, consideration should be given to more frequent monitoring of renal function.
Patients with creatinine clearance < 50 ml/min, including haemodialysis patients: There are limited data on the safety and efficacy of tenofovir disoproxil fumarate in patients with impaired renal function. Therefore, tenofovir disoproxil fumarate should only be used if the potential benefits of treatment are considered to outweigh the potential risks. In patients with severe renal impairment (creatinine clearance < 30 ml/min) and in patients who require haemodialysis use of tenofovir is not recommended. If no alternative treatment is available, the dosing interval must be adjusted and renal function should be closely monitored (see sections 4.2 and 5.2).
If serum phosphate is < 1.5 mg/dl (0.48 mmol/l) or creatinine clearance is decreased to < 50 ml/min in any patient receiving tenofovir disoproxil fumarate, renal function should be re-evaluated within one week, including measurements of blood glucose, blood potassium and urine glucose concentrations (see section 4.8, proximal tubulopathy). Consideration should also be given to interrupting treatment with tenofovir disoproxil fumarate in patients with creatinine clearance decreased to < 50 ml/min or decreases in serum phosphate to < 1.0 mg/dl (0.32 mmol/l).
Use of tenofovir disoproxil fumarate should be avoided with concurrent or recent use of a nephrotoxic medicinal product (e.g. aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir or interleukin-2). If concomitant use of tenofovir disoproxil fumarate and nephrotoxic agents is unavoidable, renal function should be monitored weekly.
Tenofovir disoproxil fumarate has not been clinically evaluated in patients receiving medicinal products which are secreted by the same renal pathway, including the transport proteins human organic anion transporter (hOAT) 1 and 3 or MRP 4 (e.g. cidofovir, a known nephrotoxic medicinal product). These renal transport proteins may be responsible for tubular secretion and in part, renal elimination of tenofovir and cidofovir. Consequently, the pharmacokinetics of these medicinal products which are secreted by the same renal pathway including transport proteins hOAT 1 and 3 or MRP 4 might be modified if they are co-administered. Unless clearly necessary, concomitant use of these medicinal products which are secreted by the same renal pathway is not recommended, but if such use is unavoidable, renal function should be monitored weekly (see section 4.5).
Bone effects: In HIV infected patients, in a 144-week controlled clinical study that compared tenofovir disoproxil fumarate with stavudine in combination with lamivudine and efavirenz in antiretroviral-naïve patients, small decreases in bone mineral density (BMD) of the hip and spine were observed in both treatment groups. Decreases in BMD of spine and changes in bone biomarkers from baseline were significantly greater in the tenofovir disoproxil fumarate treatment group at 144 weeks. Decreases in BMD of hip were significantly greater in this group until 96 weeks. However, there was no increased risk of fractures or evidence for clinically relevant bone abnormalities over 144 weeks.
Bone abnormalities (infrequently contributing to fractures) may be associated with proximal renal tubulopathy (see section 4.8).
If bone abnormalities are suspected or detected then appropriate consultation should be obtained.
Paediatric population: Viread may cause a reduction in BMD. The effects of tenofovir disoproxil fumarate-associated changes in BMD on long-term bone health and future fracture risk are currently unknown (see section 5.1).
Liver disease: Safety and efficacy data are very limited in liver transplant patients.
There are limited data on the safety and efficacy of tenofovir disoproxil fumarate in HBV infected patients with decompensated liver disease and who have a Child-Pugh-Turcotte (CPT) score > 9. These patients may be at higher risk of experiencing serious hepatic or renal adverse reactions. Therefore, hepatobiliary and renal parameters should be closely monitored in this patient population.
Exacerbations of hepatitis:
Flares on treatment: Spontaneous exacerbations in chronic hepatitis B are relatively common and are characterised by transient increases in serum ALT. After initiating antiviral therapy, serum ALT may increase in some patients (see section 4.8). In patients with compensated liver disease, these increases in serum ALT are generally not accompanied by an increase in serum bilirubin concentrations or hepatic decompensation. Patients with cirrhosis may be at a higher risk for hepatic decompensation following hepatitis exacerbation, and therefore should be monitored closely during therapy.
Flares after treatment discontinuation: Acute exacerbation of hepatitis has also been reported in patients who have discontinued hepatitis B therapy. Post-treatment exacerbations are usually associated with rising HBV DNA, and the majority appears to be self-limited. However, severe exacerbations, including fatalities, have been reported. Hepatic function should be monitored at repeated intervals with both clinical and laboratory follow-up for at least 6 months after discontinuation of hepatitis B therapy. If appropriate, resumption of hepatitis B therapy may be warranted. In patients with advanced liver disease or cirrhosis, treatment discontinuation is not recommended since post-treatment exacerbation of hepatitis may lead to hepatic decompensation.
Liver flares are especially serious, and sometimes fatal in patients with decompensated liver disease.
Co-infection with hepatitis C or D: There are no data on the efficacy of tenofovir in patients co-infected with hepatitis C or D virus.
Co-infection with HIV-1 and hepatitis B: Due to the risk of development of HIV resistance, tenofovir disoproxil fumarate should only be used as part of an appropriate antiretroviral combination regimen in HIV/HBV co-infected patients. Patients with pre-existing liver dysfunction including chronic active hepatitis have an increased frequency of liver function abnormalities during combination antiretroviral therapy and should be monitored according to standard practice. If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment must be considered. However, it should be noted that increases of ALT can be part of HBV clearance during therapy with tenofovir, see above Exacerbations of hepatitis.
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Lipodystrophy: Combination antiretroviral therapy has been associated with the redistribution of body fat (lipodystrophy) in HIV patients. The long-term consequences of these events are currently unknown. Knowledge about the mechanism is incomplete. A connection between visceral lipomatosis and protease inhibitors and lipoatrophy and nucleoside reverse transcriptase inhibitors has been hypothesised. A higher risk of lipodystrophy has been associated with individual factors such as older age, and with drug related factors such as longer duration of antiretroviral treatment and associated metabolic disturbances. Clinical examination should include evaluation for physical signs of fat redistribution. Consideration should be given to the measurement of fasting serum lipids and blood glucose. Lipid disorders should be managed as clinically appropriate (see section 4.8).
Tenofovir is structurally related to nucleoside analogues hence the risk of lipodystrophy cannot be excluded. However, 144-week clinical data from antiretroviral-naïve HIV infected patients indicate that the risk of lipodystrophy was lower with tenofovir disoproxil fumarate than with stavudine when administered with lamivudine and efavirenz.
Mitochondrial dysfunction: Nucleoside and nucleotide analogues have been demonstrated in vitro and in vivo to cause a variable degree of mitochondrial damage. There have been reports of mitochondrial dysfunction in HIV negative infants exposed in utero and/or postnatally to nucleoside analogues. The main adverse events reported are haematological disorders (anaemia, neutropenia), metabolic disorders (hyperlactataemia, hyperlipasaemia). These events are often transitory. Some late-onset neurological disorders have been reported (hypertonia, convulsion, abnormal behaviour). Whether the neurological disorders are transient or permanent is currently unknown. Any child exposed in utero to nucleoside and nucleotide analogues, even HIV negative children, should have clinical and laboratory follow-up and should be fully investigated for possible mitochondrial dysfunction in case of relevant signs or symptoms. These findings do not affect current national recommendations to use antiretroviral therapy in pregnant women to prevent vertical transmission of HIV.
Immune Reactivation Syndrome: In HIV infected patients with severe immune deficiency at the time of institution of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections, and Pneumocystis jirovecii pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary.
Osteonecrosis: Although the etiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularly in patients with advanced HIV disease and/or long-term exposure to combination antiretroviral therapy (CART). Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.
Elderly: Tenofovir disoproxil fumarate has not been studied in patients over the age of 65. Elderly patients are more likely to have decreased renal function; therefore caution should be exercised when treating elderly patients with tenofovir disoproxil fumarate.
Interaction studies have only been performed in adults.
Based on the results of in vitro experiments and the known elimination pathway of tenofovir, the potential for CYP450 mediated interactions involving tenofovir with other medicinal products is low.
Concomitant use not recommended:
Viread should not be administered concomitantly with other medicinal products containing tenofovir disoproxil fumarate.
Viread should not be administered concomitantly with adefovir dipivoxil.
Didanosine: Co-administration of tenofovir disoproxil fumarate and didanosine is not recommended (see section 4.4 and Table 1).
Renally eliminated medicinal products: Since tenofovir is primarily eliminated by the kidneys, co-administration of tenofovir disoproxil fumarate with medicinal products that reduce renal function or compete for active tubular secretion via transport proteins hOAT 1, hOAT 3 or MRP 4 (e.g. cidofovir) may increase serum concentrations of tenofovir and/or the co-administered medicinal products.
Use of tenofovir disoproxil fumarate should be avoided with concurrent or recent use of a nephrotoxic medicinal product. Some examples include, but are not limited to, aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir or interleukin-2 (see section 4.4).
Given that tacrolimus can affect renal function, close monitoring is recommended when it is co-administered with tenofovir disoproxil fumarate.
Other interactions:
Interactions between tenofovir disoproxil fumarate and protease inhibitors and antiretroviral agents other than protease inhibitors are listed in Table 1 below (increase is indicated as “↑”, decrease as “
Table 1: Interactions between tenofovir disoproxil fumarate and other medicinal products
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Studies conducted with other medicinal products: There were no clinically significant pharmacokinetic interactions when tenofovir disoproxil fumarate was co-administered with emtricitabine, lamivudine, indinavir, efavirenz, nelfinavir, saquinavir (ritonavir boosted), methadone, ribavirin, rifampicin, tacrolimus, or the hormonal contraceptive norgestimate/ethinyl oestradiol.
Tenofovir disoproxil fumarate must be taken with food, as food enhances the bioavailability of tenofovir (see section 5.2).
Pregnancy
A moderate amount of data on pregnant women (between 300-1000 pregnancy outcomes) indicate no malformations or foetal/neonatal toxicity associated with tenofovir disoproxil fumarate.
Animal studies do not indicate reproductive toxicity (see section 5.3).
The use of tenofovir disproxil fumurate may be considered during pregnancy, if necessary.
Breast-feeding
Tenofovir has been shown to be excreted in human milk. There is insufficient information on the effects of tenofovir in newborns/infants. Viread should not be used during breast-feeding.
As a general rule, it is recommended that HIV and HBV infected women do not breast-feed their infants in order to avoid transmission of HIV and HBV to the infant.
Fertility
No human data on the effect of tenofovir disoproxil fumarate are available. Animal studies do not indicate harmful effects of tenofovir disoproxil fumarate on fertility.
No studies on the effects on the ability to drive and use machines have been performed. However, patients should be informed that dizziness has been reported during treatment with tenofovir disoproxil fumarate.
a. Summary of the safety profile
HIV-1 and hepatitis B: In patients receiving tenofovir disoproxil fumarate, rare events of renal impairment, renal failure and proximal renal tubulopathy (including Fanconi syndrome) sometimes leading to bone abnormalities (infrequently contributing to fractures) have been reported. Monitoring of renal function is recommended for patients receiving Viread (see section 4.4).
HIV-1: Approximately one third of patients can be expected to experience adverse reactions following treatment with tenofovir disoproxil fumarate in combination with other antiretroviral agents. These reactions are usually mild to moderate gastrointestinal events. Approximately 1% of tenofovir disoproxil fumarate-treated patients discontinued treatment due to the gastrointestinal events.
Lactic acidosis, severe hepatomegaly with steatosis and lipodystrophy are associated with tenofovir disoproxil fumarate (see sections 4.4 and 4.8c).
Co-administration of Viread and didanosine is not recommended as this may result in an increased risk of adverse reactions (see section 4.5). Rarely, pancreatitis and lactic acidosis, sometimes fatal, have been reported (see section 4.4).
Hepatitis B: Approximately one quarter of patients can be expected to experience adverse reactions following treatment with tenofovir disoproxil fumarate, most of which are mild. In clinical trials of HBV infected patients, the most frequently occurring adverse reaction to tenofovir disoproxil fumarate was nausea (5.4%).
Acute exacerbation of hepatitis has been reported in patients on treatment as well as in patients who have discontinued hepatitis B therapy (see section 4.4).
b. Tabulated summary of adverse reactions
Assessment of adverse reactions for tenofovir disoproxil fumarate is based on safety data from clinical studies and post-marketing experience. All adverse reactions are presented in Table 2.
HIV-1 clinical studies: Assessment of adverse reactions from HIV-1 clinical study data is based on experience in two studies in 653 treatment-experienced patients receiving treatment with tenofovir disoproxil fumarate (n = 443) or placebo (n = 210) in combination with other antiretroviral medicinal products for 24 weeks and also in a double-blind comparative controlled study in which 600 treatment-naïve patients received treatment with tenofovir disoproxil 245 mg (as fumarate) (n = 299) or stavudine (n = 301) in combination with lamivudine and efavirenz for 144 weeks.
Hepatitis B clinical studies: Assessment of adverse reactions from HBV clinical study data is primarily based on experience in two double-blind comparative controlled studies in which 641 patients with chronic hepatitis B and compensated liver disease received treatment with tenofovir disoproxil 245 mg (as fumarate) daily (n = 426) or adefovir dipivoxil 10 mg daily (n = 215) for 48 weeks.
Continued treatment with tenofovir disoproxil fumarate for up to 144 weeks in these studies did not reveal any new adverse reactions and no change in the tolerability profile (nature or severity of adverse events).
Patients with decompensated liver disease: The safety profile of tenofovir disoproxil fumarate in patients with decompensated liver disease was assessed in a double-blind active controlled study (GS-US-174-0108) in which patients received treatment with tenofovir disoproxil fumarate (n = 45) or emtricitabine plus tenofovir disoproxil fumarate (n = 45) or entecavir (n = 22) for 48 weeks.
In the tenofovir disoproxil fumarate treatment arm, 7% of patients discontinued treatment due to an adverse event; 9% of patients experienced a confirmed increase in serum creatinine of
Hepatocellular carcinoma was diagnosed in 3 patients in the tenofovir disoproxil fumarate group and two patients in the tenofovir disoproxil fumarate group died during the study.
The adverse reactions with suspected (at least possible) relationship to treatment are listed below by body system organ class and frequency. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Frequencies are defined as very common (
Table 2: Tabulated summary of adverse reactions associated with tenofovir disoproxil fumarate based on clinical study and post-marketing experience
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1 This adverse reaction may occur as a consequence of proximal renal tubulopathy. It is not considered to be causally associated with tenofovir disoproxil fumarate in the absence of this condition.
2 This adverse reaction was identified through post-marketing surveillance but not observed in randomised controlled clinical trials or the tenofovir disoproxil fumarate expanded access program. The frequency category was estimated from a statistical calculation based on the total number of patients exposed to tenofovir disoproxil fumarate in randomised controlled clinical trials and the expanded access program (n = 7,319).
3 See section c. Description of selected adverse reactions for more details.
c. Description of selected adverse reactions
HIV-1 and hepatitis B:
Renal impairment: As Viread may cause renal damage monitoring of renal function is recommended (see sections 4.4 and 4.8a).
HIV-1:
Interaction with didanosine: Co-administration of tenofovir disoproxil fumarate and didanosine is not recommended as it results in a 40-60% increase in systemic exposure to didanosine that may increase the risk of didanosine-related adverse reactions (see section 4.5). Rarely, pancreatitis and lactic acidosis, sometimes fatal, have been reported.
Lipids, lipodystrophy and metabolic abnormalities: Combination antiretroviral therapy has been associated with metabolic abnormalities such as hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia and hyperlactataemia (see section 4.4).
Combination antiretroviral therapy has been associated with redistribution of body fat (lipodystrophy) in HIV patients including the loss of peripheral and facial subcutaneous fat, increased intra-abdominal and visceral fat, breast hypertrophy and dorsocervical fat accumulation (buffalo hump) (see section 4.4).
In a 144-week controlled clinical study in antiretroviral-naïve patients that compared tenofovir disoproxil fumarate with stavudine in combination with lamivudine and efavirenz, patients who received tenofovir disoproxil had a significantly lower incidence of lipodystrophy compared with patients who received stavudine. The tenofovir disoproxil fumarate arm also had significantly smaller mean increases in fasting triglycerides and total cholesterol than the comparator arm.
Immune Reactivation Syndrome: In HIV infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise (see section 4.4).
Osteonecrosis: Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term exposure to combination antiretroviral therapy (CART). The frequency of this is unknown (see section 4.4).
Lactic acidosis and severe hepatomegaly with steatosis: Lactic acidosis, usually associated with hepatic steatosis, has been reported with the use of nucleoside analogues. Treatment with nucleoside analogues should be discontinued in the setting of symptomatic hyperlactataemia and metabolic/lactic acidosis, progressive hepatomegaly, or rapidly elevating aminotransferase levels (see section 4.4).
Hepatitis B:
Exacerbations of hepatitis during treatment: In studies with nucleoside-naïve patients, on-treatment ALT elevations > 10 times ULN (upper limit of normal) and > 2 times baseline occurred in 2.6% of tenofovir disoproxil fumarate-treated patients. ALT elevations had a median time to onset of 8 weeks, resolved with continued treatment, and, in a majority of cases, were associated with a 10 copies/ml reduction in viral load that preceded or coincided with the ALT elevation. Periodic monitoring of hepatic function is recommended during treatment (see section 4.4).
Exacerbations of hepatitis after discontinuation of treatment: In HBV infected patients,
